The present invention relates to novel 1,8-naphthyridin-2(1H)-one derivatives that selectively inhibit phosphodiesterase (hereinafter, referred to as xe2x80x9cPDExe2x80x9d) IV, or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising the same. The present invention also relates to prophylactic and/or therapeutic drugs (including antiasthmatics) for diseases associated with PDE IV actions, which comprise each an effective amount of at least one member selected from the 1,8-naphthyridin-2(1H)-one derivatives and salts thereof.
PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) and intracellular cyclic GMP (cGMP) and widely distributed in vivo in various tissues and organs. Up to now, it has been known that PDEs are classified into 7 isoenzyme families, i.e., type I to VII PDEs (PDE I to VII), according to their properties. Among them, PDE IV is known to be an enzyme which is predominantly present in airway smooth muscle cells and a wide variety of inflammatory cells, i.e., neutrophils, eosinophils, lymphocytes, etc. and selectively breaks down cAMP. In addition, it has been known that an elevation of cAMP levels in airway smooth muscle cells leads to relaxation of the airway smooth muscles. An increase of cAMP levels in inflammatory cells has also been known to suppress an activation of inflammatory cells, including, for example, a release of cytotoxic proteins from eosinophils, etc.
Therefore, if PDE IV predominantly located in airway smooth muscle cells and inflammatory cells is inhibited by inhibitors selective for said isozyme form, an elevation of cAMP levels would be induced in such cells. As a result, it would be expected to elicit bronchodilator actions via relaxing airway smooth muscles and anti-inflammatory actions through suppressing inflammatory cell activation. Such selective inhibitors of PDE IV would be expected to become excellent anti-asthmatic agents.
Up to now, it has been known that theophylline which is a xanthine derivative, rolipram, which is a catechol derivative, etc. are inhibitors of PDE TV. Theophylline inhibits PDE in various tissues due to its non-selectivity for individual isozymes, thereby exerting not only a bronchodilator activity to be targeted but also extra actions on heart, CNS, etc. Although rolipram is observed to be selective for PDE IV, it is easily transferred into the CNS due to its property of being absorbed. Therefore, rolipram has a drawback that it induces adverse central side-actions such as an emetic action.
Under these circumstances, in order to find out pharmaceutical drugs having an excellent anti-asthmatic efficacy via minimizing undesirable side-actions in tissues and organs other than bronchial smooth muscles and inflammatory cells, inhibitors with improved selectivity for PDE IV have been screened and examined.
For instance, with an aim at such inhibitors, various compounds including diazepinoindoles (JP, A, 10-507447 (1998)), tri-substituted phenyl derivatives (JP, A, 10-504530 (1998), JP, A, 10-503174 (1998), JP, A, 10-503173 (1998), etc.), naphthalene derivatives (JP, A, 10-226647 (1998)), etc., have been proposed.
Besides these, for the purpose of developing not only anti-asthmatics but also pharmaceutical drugs for preventing and treating a wide range for diseases, PDE IV-inhibitory compounds having a naphthyridine ring have been proposed in WO 94/12499, A1; JP, A, 7-10875 (1995); WO 96/6843, A1; JP, A, 11-106385 (1999); etc.
Further, JP, A, 63-159382 (1988) discloses 1-substituted naphthyridine derivatives having, on the position 3, a substituent selected from alkyl, cycloalkyl, phenyl, phenylalkyl, etc., which are deemed useful in the treatment of allergy, inflammation, and the like, though no mention is made of PDE IV-inhibiting actions.
Such compound groups are, however, unsatisfactory in view of solving the aforementioned problems. There is still a demand for anti-asthmatics which exert more selective PDE IV-inhibiting actions and have advantageous properties from aspects regarding efficacy and safety.
For instance, over the past decade, many pharmaceutical companies have focused on the inhibition of PDE IV for the treatment of asthma. The biology of the PDE IV isozyme and the structure-activity relationship of already-reported inhibitors have recently been reviewed in the literature. In such processes, it has been pointed out that in general the therapeutic utility of selective PDE IV inhibitors, such as the prototypical agent rolipram, have been hampered by nausea and emesis limiting their therapeutic potential (J. Med. Chem., 41: 2268 to 2277 (1998)).
The present inventors have conducted an extensive research on various compounds in order to solve the above problems. As a result, the present inventors have succeeded in producing novel 1,8-naphthyridin-2(1H)-one derivatives which exert selective inhibition against PDE IV. Further, the present inventors have found that the compounds of the present invention are not only unexpectedly advantageous over the conventional PDE IV inhibitors but also qualified as potent inhibitors of PDE IV from aspects of pharmacological action and safety, and succeeded in accomplishing this invention.
The present invention, as described hereinbelow, encompasses 1,8-naphthyridin-2(1H)-one derivative compounds having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridin-2(1H)-one nucleus and pharmaceutical compositions comprising an effective amount of the said compound. Since the compounds of the invention are naphthyridine derivatives having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridine nucleus, it is apparent that the inventive compounds are structurally different from 1-substituted naphthyridine derivatives disclosed in JP, A, 63-159382 (1988). As described hereinbelow, the compounds of the invention are also distinct from the compounds disclosed in JP, A, 63-159382 (1988) because their PDE IV-inhibiting activity is significantly superior to that of the prior art compounds.
The present invention provides the following:
1) A compound of the formula (1): 
wherein:
A is an unsubstituted or optionally substituted 5 or 6 membered heteroaryl group or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ring,
B is carbon or nitrogen,
R1 is hydrogen, lower alkyl, trifluoromethyl, hydroxyl, lower alkoxy, a residue derived from a carboxylic acid or a derivative thereof, amino, or an amino nitrogen-containing group,
R2 is hydrogen, halogen, cyano, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trifluoromethyl, hydroxyl, lower alkoxy, a residue derived from a carboxylic acid or a derivative thereof, amino, or an amino nitrogen-containing group, and
m is an integer of from 1 to 8, both inclusive; or a pharmaceutically acceptable salt thereof.
2) The compound according to the above 1), wherein A is a 5 or 6 membered heteroaryl group and B is carbon; or a pharmaceutically acceptable salt thereof.
3) The compound according to the above 2), wherein A is pyridyl, 1-oxypyridyl, thienyl, furyl, or thiazolyl; or a pharmaceutically acceptable salt thereof.
4) The compound according to the above 2), wherein A is pyridyl or 1-oxypyridyl, and m is from 1 to 5, both inclusive; or a pharmaceutically acceptable salt thereof.
5) The compound according to the above 1), wherein A is a 5 or 6 membered heteroaryl group, and B is nitrogen; or a pharmaceutically acceptable salt thereof.
6) The compound according to the above 5), wherein A is pyridyl, 1-oxypyridyl, thienyl, furyl, or thiazolyl; or a pharmaceutically acceptable salt thereof.
7) The compound according to the above 1), wherein A is a fused benzene ring in which any of the above-defined 5 or 6 membered heteroaryl groups is fused to a benzene ring, and B is carbon; or a pharmaceutically acceptable salt thereof.
8) The compound according to the above 7), wherein A is benzothiazolyl; or a pharmaceutically acceptable salt thereof.
9) The compound according to the above 1), wherein A is a fused benzene ring in which any of the above-defined 5 or 6 membered heteroaryl groups is fused to a benzene ring, and B is nitrogen; or a pharmaceutically acceptable salt thereof.
10) The compound according to the above 9), wherein A is benzothiazolyl; or a pharmaceutically acceptable salt thereof.
11) The compound according to any of the above 1) to 10), wherein R1 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.
12) The compound according to any of the above 1) to 11), wherein R2 is hydrogen, halogen, cyano, nitro, lower alkylthio, lower alkylsulfinyl, or lower alkylsulfonyl; or a pharmaceutically acceptable salt thereof.
13) 1-(3-Nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin -2(1H)-one.
14) 1-(3-Nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one.
15) 1-(3-Methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one.
16) 1-(Pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one.
17) A pharmaceutical composition which comprises an effective amount of a compound according to any of the above 1) to 16) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
18) A phosphodiesterase IV inhibitor comprising an effective amount of a compound according to any of the above 1) to 16) or a pharmaceutically acceptable salt thereof.
19) An anti-asthmatic comprising an effective amount of a compound according to any of the above 1) to 16) or a pharmaceutically acceptable salt thereof.
20) A drug for the prophylaxis and/or treatment of at least one member selected from diseases or abnormal conditions related to phosphodiesterase IV activity, said drug comprising an effective amount of a compound according to any of the above 1) to 16) or a pharmaceutically acceptable salt thereof.
21) A drug comprising an effective amount of a compound according to any of the above 1) to 16) or a pharmaceutically acceptable salt thereof, said drug for preventing and/or treating at least one disease or abnormal condition selected from the group consisting of:
(1) respiratory diseases, including bronchial asthma (including chronic bronchial asthma and atopic asthma), acute bronchitis, chronic bronchitis, asthmatic bronchitis, pneumonic diseases, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and the like;
(2) inflammatory diseases, including atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocyclitis, gingivitis, periodontitis, dentoalveolitis, gastritis, ulcerative colitis, Crohn""s disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (such as myasthenia gravis, multiple sclerosis and neuritis), hepatitis, scar tissue formation, nephritis (including proliferative nephritis), peritonitis, pleurisy, scleritis, scleroderma, scalds or burns, and the like;
(3) systemic or local joint diseases, including osteoarthritis, gouty arthritis, rheumatoid arthritis, malignant rheumatism, psoriatic arthritis, and the like;
(4) inflammatory conditions associated with organ transplantation, etc., including reperfusion injury, graft versus host reaction, and the like;
(5) diseases related to urination, including diabetes insipidus, urethritis, urinary incontinence, cystitis, irritable bladder, neurogenic bladder, uremia, uriniferous tubular disorder, pollakiuria, ischuria, and the like;
(6) diseases or abnormal conditions related to tumor necrosis factor (TNF) (for example, TNF-xcex1, etc.) and other cytokines (for example, IL-1, IL-4, IL-6, etc.), including psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, septicemia, septic shock, endotoxic shock, gram negative bacillus sepsis, toxic shock syndrome, nephritis, hepatitis, infection (induced by bacteria and viruses), circulatory failure (heart failure, arteriosclerosis, myocardial infarction, cerebral apoplexy), and the like;
(7) proliferative diseases, including malignant tumors, leukemia, proliferative dermal diseases (keratosis and various types of dermatitides), connective tissue diseases and the like;
(8) diseases related to nervous function abnormality, including impaired learning, memory and recognition related to neurodegenerative disorders such as Alzheimer""s disease and Parkinson""s disease, multiple lateral sclerosis, senile dementia, amyotrophic lateral sclerosis, acute demyelinating neuritis, muscular dystrophy, and the like;
(9) diseases related to abnormality of mental functions, including manic-depressive psychosis, schizoid, anxiety, panic, and the like;
(10) diseases demanding protection of nerves and cells, including cardiac arrest, spinal cord injury, intermittent claudication, ischemic diseases (including angina pectoris, cardiac infarction, cerebral apoplexy, head injury, etc.) and the like;
(11) endocrine diseases, including not only diabetes but also diabetic retinopathy, diabetic nephropathy, diabetic neurosis, amyloidosis, pancreatitis, thyroiditis, obesity, prostatomegaly, and the like;
(12) autoimmune diseases, including systemic lupus erythematosus (SLE), atrophic gastritis, thyroid diseases, glomerular nephritis, orchitis, adrenal diseases, hemolytic anemia, oophoritis, and the like;
(13) cardiovascular diseases, including hypertension, angina pectoris, heart failure, myocarditis, external epicarditis, endocarditis, valvulitis, and the like;
(14) vessel and blood system diseases, including angiitis, aneurysm, endoangiosis, thromboangiitis, granulomatosis, cerebrovascular angiitis, arteriosclerosis, periangitis, leukopenia, thrombocytopenia, Boeck""s sarcoid, and the like;
(15) diseases related to immune reactions or allergic responses, including contact dermatitis, serum sickness, drug allergy, Goodpasture""s syndrome, lymphoma, rheumatic fever, AIDS, anaphylactic shock and the like; and
(16) other diseases, disorders or abnormal states, including glaucoma, spastic paralysis, impotence, diseases or illness accompanied with pain (contusion, headache, etc.), neck-shoulder-arm syndrome, nephropathy, renal insufficiency, hepatic insufficiency, obesity, etc.
22) The drug according to the above 20) or 21) for preventing and/or treating at least one disease or abnormal state selected from the group consisting of:
(1) respiratory diseases selected from the group consisting of bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease; and acute respiratory distress syndrome (ARDS); and
(2) inflammatory diseases selected from the group consisting of atopic dermatitis; conjunctivitis; urticaria; acquired immunodeficiency syndrome (AIDS); keloid formation; rhinitis; iridocyclitis; gingivitis; periodontitis; dentoalveolitis; gastritis; ulcerative colitis; Crohn""s disease; gastrointestinal ulcer; esophagitis; myositis; encephalitis such as myasthenia gravis, multiple sclerosis and neuritis; hepatitis; scar tissue formation; nephritis including proliferative nephritis; peritonitis; pleurisy; scleritis; scleroderma; and scalds or burns.
23) The agent or drug according to any of the above 18) to 22) which is selected from the group consisting of oral pharmaceutical forms, injections and inhalants.
24) The agent or drug according to any of the above 18) to 22) which is selected from the group consisting of ointments, patches, solutions for external use, eyedrops, nose drops (collunaria) and suppositories.
The above objectives and other objectives, features, advantages, and aspects of the present invention are readily apparent to those skilled in the art from the following disclosures. It should be understood, however, that the description of the specification including the following best modes of carrying out the invention, examples, etc. is illustrating preferred embodiments of the present invention and given only for explanation thereof. It will become apparent to the skilled in the art that a great number of variations and/or alterations (or modifications) of this invention may be made based on knowledge from the disclosure in the following parts and other parts of the specification without departing from the spirit and scope thereof as disclosed herein. All of the patent publications and reference documents cited herein for illustrative purposes are hereby incorporated by reference into the present disclosure.
The present invention provides compounds, or salts thereof, having an unsubstituted or optionally substituted 5 to 6 membered heteroaryl group or a fused ring in which any of the heteroaryl groups is contained (for example, a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring), via a chain comprised of 1 to 8 members of methylene, on the position 3 of a 1,8-naphthyridin-2(1H)-one ring, which possess advantageous biological properties, and pharmaceutical compositions comprising at least one member selected from the aforementioned compounds and pharmaceutically acceptable salts thereof. The compounds or salts thereof are utilizable for their selective PDE IV-inhibiting actions. Therefore, the present invention also provides drugs for preventing and/or treating at least one member selected from diseases, disorders, and abnormal conditions related to an activity of PDE IV. It should be noted that any of 1,8-naphthyridin-2(1H)-one rings known in the art prior to the present case may be adoptable without any limitations wherein such 1,8-naphthyridin-2(1H)-one rings may have any of all substituents known to be placed on any of positions other than the position 3 of the 1,8-naphthyridin-2(1H)-one ring.
A preferred embodiment of the present invention is as follows:
The definitions for the compounds of the above-defined formula (1) will be given below in detail.
As used herein, the term xe2x80x9ca 5 or 6 membered heteroaryl group or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ringxe2x80x9d refers to a 5 or 6 membered heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of N, S, and O; or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ring. Representatives of such heteroaryl groups and fused benzene rings include pyrrolyl, pyridyl, 1-oxypyridyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, indolyl, quinolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, etc. Among them, preferred groups include pyridyl, 1-oxypyridyl, thienyl, furyl, thiazolyl, and benzothiazolyl. Particularly, pyridyl and 1-oxypyridyl are preferable. Examples of the pyridyl are 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.
The heteroaryl group and the fused benzene ring may be unsubstituted or optionally substituted with one or more substituents. The substituents include lower alkyl, lower alkoxy, hydroxyl, halogen, nitro, halogen-substituted lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, a residue derived from carboxylic acids and derivatives thereof, such as alkoxycarbonyl, and an amino nitrogen-containing radical such as di-lower alkylamino.
As used herein, the term xe2x80x9clower alkylxe2x80x9d refers to alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.
The term xe2x80x9chalogenxe2x80x9d as used herein refers to fluorine, chlorine, bromine, and the like.
The term xe2x80x9clower alkylthioxe2x80x9d refers to alkylthio containing 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, and isopropylthio.
The term xe2x80x9clower alkylsulfinylxe2x80x9d refers to alkylsulfinyl containing 1 to 4 carbon atoms, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, and isopropylsulfinyl.
The term xe2x80x9clower alkylsulfonylxe2x80x9d refers to alkylsulfonyl containing 1 to 4 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d refers to alkoxy containing 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, and isopropoxy.
Preferred compounds according to the present invention have the structural formula (1). Still more preferred compounds according to the present invention have the structural formula (1) wherein A is pyridyl or 1-oxypyridyl; and m is selected from 1 to 5.
Representative examples of compounds of the invention include the following:
1-(3-Nitrophenyl)-3-(pyridin-2-ylmethyl)-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin-2(1H)-one,
1-(3-Cyanophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(pyridin-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(pyridin-3-yl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(1-oxypyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Cyanophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Chlorophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Methylsulfinylphenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Methylsulfonylphenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Methylsulfonylphenyl)-3-[3-(1-oxypyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
7-Methyl-1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
7-Methyl-1-(3-methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[4-(pyridin-2-yl)butyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[4-(pyridin-3-yl)butyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[4-(pyridin-4-yl)butyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[5-(pyridin-2-yl)pentyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[5-(pyridin-3-yl)pentyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[5-(pyridin-4-yl)pentyl]-1,8-naphthyridin-2(1H)-one
1-(3-Nitrophenyl)-3-[6-(pyridin-4-yl)hexyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[7-(pyridin-4-yl)heptyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(2-thienyl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(3-thienyl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(2-furyl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(3-furyl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(thiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[2-(benzothiazol-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[3-(benzothiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(3-Nitrophenyl)-3-[4-(benzothiazol-2-yl)butyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-2-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-3-yl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-3-yl)-3-[4-(pyridin-4-yl)butyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-4-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one,
1-(Pyridin-3-yl)-3-[2-(benzothiazol-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one, and
1-(Pyridin-3-yl)-3-[2-(benzothiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one.
As used herein, xe2x80x9cthe compound(s) of the present inventionxe2x80x9d may include salts thereof, hydrates and solvates thereof, a variety of prodrug forms derived from functional groups existing in compound molecules. The prodrugs of the compounds according to the present invention include those compounds which can be transformed in vivo, for example, by metabolic processes, including hydrolysis, oxidation, reduction, trans-esterification, and the like, to yield the parent compounds of the formula (1), etc. Representatives of such prodrugs are ester-, ether-, amide-, alcohol-, and amine-derivatives thereof. Preferred compounds according to the present invention are potently active in the inhibition of IV-type phosphodiesterases.
Some of the compounds of formula (1) may exist in more than one tautomeric form. This invention extends to all tautomeric forms. The compounds of the instant invention may also contain one or plural asymmetric carbon atoms and thus give rise to optical isomers such as (R)- and (S)-isomers, racemates, diastereoisomers, etc. The present invention includes all such possible isomers, and their racemic and resolved, enantiomerically pure forms, as well as all mixtures thereof. The compounds of the invention may be isolated in the form of hydrates, solvates with, for example, ethanol and the like, and a variety of crystalline substances.
The present invention also encompasses pharmaceutically acceptable salts of the naphthyridine derivative having the formula (1). Such salts include those formed from any of medically or pharmaceutically utilizable non-toxic or low toxic inorganic or organic acids. Examples of the salts are hydrochloride, hydrobromate, sulfate, acetate, propionate, citrate, succinate, tartrate, methanesulfonate, p-toluenesulfonate, etc.
The compounds of the present invention can be prepared by one of various routes. For instance, the compounds of the formula (1) can be prepared by one of the following schemes or modifications thereof: 
In the aforementioned Scheme, the compounds of the formula (1) wherein A, B, R1, R2 and m, all have the meanings given above can be prepared by condensing a compound of the formula (2) wherein B, R1 and R2, all have the meanings given above with a compound of the formula (3) wherein R3 is lower alkyl, and m and A, both have the meanings given above in the presence of a base.
In the compounds of the formula (3), the lower alkyl for R3 has the same meaning as in the above-defined compounds of the formula (1) and refers to alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.
Bases used in this condensation may include alkali metal amides, alkali metal hydrides, alkyl lithium, aryl lithium, and the like. Examples of the base are lithium diisopropylamide (LDA), sodium bistrimethylsilylamide, potassium hydride, methyl lithium, phenyl lithium, etc. The reaction can be conducted in the presence of or in the absence of a solvent. When the reaction is conducted in solvents, it is often convenient to use conventional solvents which are free from any adverse action on the reaction. Preferred examples of such solvents are tetrahydrofuran (THF), diethyl ether, methylene chloride, etc. The reaction temperature range is about xe2x88x9280 to 100xc2x0 C. and preferably about xe2x88x9280xc2x0 C. to room temperature.
In the aforementioned Scheme (I), the compounds of the formula (2) can be prepared by one of known methods (e.g., JP, A, 62-158281 (1987); JP, A, 62-228076 (1987); etc.) or modifications thereof.
In the aforementioned Scheme (I), the compounds of the formula (3) can be prepared, for example, by one of the synthetic routes described herein. The disclosures given below illustrate the preparation of compounds of the formula (3) wherein A is pyridyl. For instance, the compounds of the formula (3) wherein A is pyridyl and m is 1, 2 or 3, can be prepared according to one of Schemes (IIa), (IIb) and (IIc) outlined as follows: 
Described below is an illustration for each production process.
A pyridylacrylic acid ester (6) can be prepared by condensing a pyridine aldehyde (4) with a diethylphosphono acetic acid lower alkyl ester of the formula (5) wherein R3 has the same meaning as defined above in the presence of a base such as sodium hydride. Next, a compound of the formula (3) wherein A is pyridyl and m is 1 (Compound (3a)) can be prepared by reduction of the compound (6). The reduction of the compound (6) can be effected generally by hydrogenation in the presence of a suitable catalyst such as palladium on carbon.
A compound (9) can be prepared by addition of ethyl malonate (8) to vinylpyridine (7) in the presence of a suitable base such as sodium methoxide or sodium ethoxide. Next, the compound (9) can be hydrolyzed under acidic conditions (for example, with conc. hydrochloric acid) and then decarboxylated to give a carboxylic acid derivative (10). A compound of the formula (3) wherein A is pyridyl and m is 2 (Compound (3b) can be prepared by esterification of the carboxylic acid derivative (10) with a lower alkyl alcohol of the formula: R3OH wherein R3 has the same meaning as defined above. It should be noted that the aforementioned compounds (3b) may be prepared by processes entirely different from the Scheme (IIb), i.e., they can be prepared according to the procedure of Synthetic Example 7 given below.
A compound (12) can be prepared by condensing a pyridine aldehyde (4) with a diethylphosphonocrotonic acid lower alkyl ester of the formula (11) wherein R3 has the same meaning as defined above in the presence of a base such as LDA. Next, a compound of the formula (3) wherein A is pyridyl and m is 3 (Compound (3c)) can be prepared by reduction (for example, catalytic reduction) of the compound (12). In this Scheme, the catalytic reduction may be effected by techniques similar to the reduction in the Scheme (IIa).
The compounds of the formula (3) wherein A is pyridyl and m is selected from 4 to 8 (Compound (3d)), can be prepared according to the Scheme (IId) outlined as follows: 
wherein m is an integer selected from 4 to 8, both inclusive.
A bromoalkyl carboxylic acid (13) is reacted with triphenylphosphine to produce a phosphonium salt (14) which is then treated with a base prepared from sodium hydride and dimethylsulfoxide (DMSO) to give a phosphorane. The resultant phosphorane is reacted with a pyridine aldehyde (4) followed by treatment with chloroacetonitrile. The resulting cyanomethyl ester derivative (15) is subjected to a trans-esterification using a lower alkyl alcohol of the formula: R3OH wherein R3 has the same meaning as defined above in the presence of a catalytic amount of triethylamine to produce a lower alkyl ester derivative (16) which is then reduced to give a compound of the formula (3) wherein A is pyridyl and m is selected from 4 to 8 (Compound (3d)). It should be noted that the reduction of the lower alkyl ester derivative (16) may be conducted by techniques similar to the catalytic reduction in the Scheme (IIa).
The aforementioned Schemes (IIa) to (IId) and suitable modifications thereof are adoptable for preparing compounds of the formula (3) wherein A is a 5 or 6 membered heteroaryl group or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, other than pyridyl. For the Scheme (I), it should be noted that the compounds of the formula (3) wherein A is benzothiazolyl can be prepared according to methods known to those skilled in the art (e.g., JP, A, 8-208631 (1996), etc.).
The compounds of the present invention so prepared may be isolated or purified as free forms per se or in the form of salts after being subjected to conventional salt-forming treatments. The isolation and purification can be effected by adaptations of ordinary chemical operations including, for example, extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatographic techniques, etc. various isomers can be separated by conventional methods utilizing a difference of physico-chemical properties among such isomers. For example, stereochemically pure isomers can be obtained from racemic mixtures by an ordinary racemic resolution (for example, by first converting said racemic mixtures with usual optically-active acids (including tartaric acid, etc.) to diastereomer salts followed by optical resolution, etc.). Diastereomers can be separated by ordinary methods such as selective crystallization or chromatographic techniques. Pure optically-active isomeric forms of the compounds of the present invention may also be obtained from the pure optically-active isomeric forms of the appropriate starting materials and intermediates.
The compounds of the present invention are potent inhibitors of PDE IV. The compounds of the present invention are thus of use in the prophylaxis and treatment of diseases and abnormal states related to PDE IV actions. In particular, the compounds of the present invention are effective as prophylactic or therapeutic agents for diseases and conditions associated with an abnormal enzymatic or catalytic activity of PDE IV. The compounds of the present invention are of use in medicine, especially in the prophylaxis and treatment of:
(1) respiratory diseases, including, for example, bronchial asthma (including chronic bronchial asthma and atopic asthma), acute bronchitis, chronic bronchitis, asthmatic bronchitis, pneumonic diseases, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and the like;
(2) inflammatory diseases, including, for example, atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocyclitis, gingivitis, periodontitis, dentoalveolitis, gastritis, ulcerative colitis, Crohn""s disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (such as myasthenia gravis, multiple sclerosis and neuritis), hepatitis, scar tissue formation, nephritis (including proliferative nephritis), peritonitis, pleurisy, scleritis, scleroderma, scalds or burns, and the like;
(3) systemic or local joint diseases, including, for example, osteoarthritis, gouty arthritis, rheumatoid arthritis, malignant rheumatism, psoriatic arthritis, and the like;
(4) inflammatory conditions associated with organ transplantation, etc., including, for example, reperfusion injury, graft versus host reaction, and the like;
(5) diseases or symptoms related to urination, including, for example, diabetes insipidus, urethritis, urinary incontinence, cystitis, irritable bladder, neurogenic bladder, uremia, uriniferous tubular disorder, pollakiuria, ischuria, and the like;
(6) diseases or abnormal conditions related to tumor necrosis factor (TNF) (for example, TNF-xcex1, etc.) and other cytokines (for example, IL-1, IL-4, IL-6, etc.), including, for example, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, septicemia, septic shock, endotoxic shock, gram-negative bacillus sepsis, toxic shock syndrome, nephritis, hepatitis, infection (induced by bacteria and viruses), circulatory failure (heart failure, arteriosclerosis, myocardial infarction, cerebral apoplexy), and the like;
(7) proliferative diseases, including, for example, malignant tumors, leukemia, proliferative dermal diseases (keratosis and various types of dermatitides), connective tissue diseases and the like;
(8) diseases related to nervous function abnormality, including, for example, impaired learning, memory and recognition associated with neurodegenerative disorders such as Alzheimer""s disease and Parkinson""s disease, multiple lateral sclerosis, senile dementia, amyotrophic lateral sclerosis, acute demyelinating neuritis, muscular dystrophy, and the like;
(9) diseases related to abnormality of mental functions, including, for example, manic-depressive psychosis, schizoid, anxiety, panic, and the like;
(10) diseases demanding protection of nerves and cells, including, for example, cardiac arrest, spinal cord injury, intermittent claudication, ischemic diseases (including, for example, angina pectoris, cardiac infarction, cerebral apoplexy, head injury, etc.) and the like;
(11) endocrine diseases, including not only diabetes but also diabetic retinopathy, diabetic nephropathy, diabetic neurosis, amyloidosis, pancreatitis, thyroiditis, obesity, prostatomegaly, and the like;
(12) autoimmune diseases, including, for example, systemic lupus erythematosus (SLE), atrophic gastritis, thyroid diseases, glomerular nephritis, orchitis, adrenal diseases, hemolytic anemia, oophoritis, and the like;
(13) cardiovascular diseases, including, for example, hypertension, angina pectoris, heart failure, myocarditis, external epicarditis, endocarditis, valvulitis, and the like;
(14) vessel and blood system diseases, including, for example, angiitis, aneurysm, endoangiosis, thromboangiitis, granulomatosis, cerebrovascular angiitis, arteriosclerosis, periangitis, leukopenia, thrombocytopenia, Boeck""s sarcoid, and the like;
(15) diseases related to immune reactions or allergic responses, including, for example, contact dermatitis, serum sickness, drug allergy, Goodpasture""s syndrome, lymphoma, rheumatic fever, AIDS, anaphylactic shock and the like; and
(16) other diseases, disorders or abnormal states, including, for example, glaucoma, spastic paralysis, impotence, diseases or illness accompanied with pain (contusion, headache, etc.), neck-shoulder-arm syndrome, nephropathy, renal insufficiency, hepatic insufficiency, obesity, etc. It is known that the aforementioned diseases and abnormal conditions would be related to an activity of PDE IV.
Particularly, the compounds of the present invention act as prophylactic and/or therapeutic drugs for:
(a) respiratory diseases (including, for example, bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease; acute respiratory distress syndrome (ARDS); etc.);
(b) inflammatory diseases (including, for example, atopic dermatitis; conjunctivitis; urticaria; acquired immunodeficiency syndrome (AIDS); keloid formation; rhinitis; iridocyclitis; gingivitis; periodontitis; dentoalveolitis; gastritis; ulcerative colitis; Crohn""s disease; gastrointestinal ulcer; esophagitis; myositis; encephalitis (e.g., myasthenia gravis, multiple sclerosis and neuritis); hepatitis; scar tissue formation; nephritis including proliferative nephritis; peritonitis; pleurisy; scleritis; scleroderma; scalds or burns; etc.); and
(c) diseases or abnormal conditions related to tumor necrosis factor (TNF) and other cytokines (e.g., IL-1, IL-6, etc.) (including, for example, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, septicemia, septic shock, endotoxic shock, gram-negative bacillus sepsis, toxic shock syndrome, nephritis, hepatitis, infection (induced by bacteria and viruses), circulatory failure (e.g., heart failure, arteriosclerosis, myocardial infarction, cerebral apoplexy, etc.), and the like).
More preferably, the compounds of the present invention act as drugs for preventing and/or treating at least one disease or abnormal state selected from respiratory diseases (including, for example, bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease; acute respiratory distress syndrome (ARDS); etc.). Among them, the compounds of the present invention are most preferably effective as prophylactic and/or therapeutic drugs for bronchial asthma.
The compounds of the present invention are particularly useful in treating or preventing diseases or abnormal states because they are significantly less emetic than the prior art PDE IV inhibitors. The compounds of the present invention are effective in treating or preventing diseases or abnormal states wherein they are required to be administered systemically or locally.
Thus, the present invention encompasses pharmaceutical compositions comprising an effective amount of at least one member selected from the above-defined compounds (1) and pharmaceutically acceptable salts thereof, and not only inhibitors of PDE IV but also pharmaceutical drugs for preventing or treating at least one member selected from diseases and abnormal conditions related to an activity of PDE IV, more preferably anti-asthmatic agents.
As aforementioned, since PDE IV is predominantly in vivo located in airway smooth muscle cells and inflammatory cells, the compounds of the present invention inhibit selectively PDE IV in these cells, thereby exerting a bronchodilator action via relaxing airway smooth muscles, together with an anti-inflammatory action through suppressing inflammatory cell activation. Hence, the compounds of the present invention are widely effective in ameliorating a variety of undesirable responses and symptoms raised with regard to asthma.
The following disclosure is to illustrate an anti-asthmatic efficacy of the compounds of the present invention in detail:
It is known that a series of responses, such as an immediate asthmatic response, a delayed asthmatic response, and a hypersensitive airway response, are induced when an asthmatic patient inhales antigens which cause the disease.
First, the immediate asthmatic response that begins immediately after inhalation of antigens is a typical airway smooth muscle constrictive reaction induced by chemical mediators (including histamine, leukotrienes, etc.) which are released from mast cells as a result of antigen-antibody interactions. Later the delayed asthmatic response is observed, which occurs within 4 to 24 hours after the inhalation of antigens. For its pathological states, an infiltration of inflammatory cells into lung tissues, airway mucosa edema, etc. are observed. Thereafter, the hypersensitive airway response is further elicited, which occurs within 1 to 14 days after the inhalation of antigens and is a state wherein the airway reactivity is increased. In such a stage, even quite mild stimuli lead to constriction of the airway and occurrence of serious airway obstruction.
As aforementioned, various responses and symptoms appear in asthma. The compounds of the present invention can exert an excellent inhibitory and/or ameliorating activity on such responses and symptoms at each stage, relying on their bronchodilator and anti-inflammatory actions based on the inhibition of PDE IV.
In addition, since the PDE-inhibiting action exerted by the compounds of present invention is highly selective against PDE IV but less selective for other isoenzymes located in certain tissues such as CNS and heart, it may be possible to avoid side-effects (for example, spasm, tachycardia, palpitation, etc.) caused by the inhibition of these isoenzymes when the present invention is applied.
Diseases and abnormal states to be targeted by the therapy using the compounds of the present invention include the aforementioned diseases and abnormal conditions, preferably diseases and abnormal conditions accompanied with respiratory dysfunctions and inflammation at the area of bronchus and airway. Embodiments of such diseases include bronchial asthma, chronic bronchial asthma, acute bronchitis, chronic bronchitis, asthmatic bronchitis, pulmonary emphysema, and other bronchus and airway inflammatory states, etc. It is noted that chronic bronchitis and pulmonary emphysema may also be generically termed chronic obstructive pulmonary disease.
For patients with the foregoing diseases, disorders, and abnormal states, the compounds of the present invention can be used independently without any additives, but preferably in admixture with any of pharmaceutically acceptable additives. The compounds of the present invention may be orally, parenterally (including by injection), topically (including by inhalation) administered as pharmaceutical compositions or formulations. One or more components selected from known pharmaceutical additives (hereinafter also referred to xe2x80x9cpharmaceutical ingredient(s)xe2x80x9d) can be employed in the aforementioned pharmaceutical compositions or formulations for any of administration routes. Embodiments of such known pharmaceutical additives may be suitably selected, according to administration routes and applications of pharmaceutically formulated forms, from components as disclosed in, for example,
(1) xe2x80x9cIyakuhin Tenkabutsu Handbook (Handbook of PHARMACEUTICAL EXCIPIENTS)xe2x80x9d, Maruzen Publishing Company, Japan (1989);
(2) xe2x80x9cIyakuhin Tenkabutsu Jiten (Pharmaceutical Excipient Dictionary)xe2x80x9d, First Edition, K.K. Yakuji Nippo Sha, Japan (1994);
(3) xe2x80x9cIyakuhin Tenkabutsu Jiten Tsuiho (Pharmaceutical Excipient Dictionary, Supplement)xe2x80x9d, First Edition, K.K. Yakuji Nippo Sha, Japan (1995); and
(4) xe2x80x9cYakuzaigaku (Pharmaceutics)xe2x80x9d, 5th Edition, K.K. Nankodo, Japan (1997).
For oral administration, the aforementioned additives are any pharmaceutical ingredients as long as they are suitable for oral drugs and the intended purposes according to the present invention. Usually, the pharmaceutical additive is selected from conventional pharmaceutical ingredients such as vehicles, binders, disintegrants, lubricants and coating agents. The oral formulations of the present invention include tablets, capsules, granules, fine granules, powders, syrups, etc. The oral drug includes controlled-release system preparations wherein the in vivo release of the compound of the present invention which is contained as the active ingredient is controlled using any of known pharmaceutical ingredients (for example, immediate-release preparations, sustained-release preparations, etc.). The aforementioned oral drug may include enteric preparations. In some cases, it is rather preferable that the oral drugs are prepared in the form of such enteric preparations. Such enteric preparations include coated or matrix formulations using any of enteric coating agents such as cellulose phthalate, hydroxypropyl methylcellulose phthalate, and methyl methacrylate-methacrylic acid copolymers, among the coating agents given below, and capsule formulations wherein any of the enteric coating agents is contained as an ingredient for their coat.
Embodiments of pharmaceutical ingredients as used for the aforementioned oral drugs are listed below but not limited to:
1) representatives of fillers:
lactose, starch (including corn starch), crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carboxymethylcellulose sodium, dextrin, sucrose, glucose, mannitol, calcium carbonate, calcium phosphate, calcium sulfate, calcium silicate, Crosspovidone, dried yeast, and soybean oil unsaponifiable fractions;
2) representatives of binders:
starch (including corn starch), gelatin, gum acacia, hydroxypropyl cellulose (HPC), methylcellulose (MC), carboxymethylcellulose (CMC), polyvinyl-pyrrolidone (PVP), ethylcellulose (EC), glucose, and sucrose;
3) representatives of disintegrants:
starch (including corn starch), agar, gelatin, CMCxe2x80x94Na, CMCxe2x80x94Ca, crystalline cellulose, crystalline cellulose-carboxymethylcellulose sodium, low-substituted HPC, Crosspovidone, calcium carbonate, and sodium bicarbonate;
4) representatives of lubricants:
magnesium stearate, hydrogenated vegetable oil, talc, Macrogol, and light anhydrous silicic acid; and
5) representatives of coating agents:
sucrose, HPC, shellac, gelatin, glycerin, sorbitol, EC, HPC, hydroxypropyl methylcellulose (HPMC), PVP, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymers, and titanium oxide.
For injection, the additives include pharmaceutical ingredients suitable for aqueous or non-aqueous injections. Usually, the additive is selected from conventional pharmaceutical ingredients such solubilizers, solution adjuvants, suspending agents, buffers (pH regulators), stabilizers and preservatives. In addition, it may be selected from conventional ingredients suitable for preparing powders for injection, which are used in solution or suspension when administered.
Representatives of said solubilizers for injections include water for injection, physiological saline, Ringer""s solution, vegetable oil (for example, olive oil, sesame oil, soybean oil), ethanol, propylene glycol, polyethylene glycol, glycerin, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc. Representatives of said solution adjuvants, suspending agents, buffers (pH regulators), stabilizers and preservatives for injections include polyethoxylated hydrogenated castor oil, ethylene diamine, benzyl alcohol, Polysorbate 80, carboxymethylcellulose sodium, sodium hydroxide, sodium citrate, sodium acetate, potassium dihydrogen phosphate, sodium hydrogen sulfite, ascorbic acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc. Representatives of said constituents for powdered injections include glucose, sorbitol, etc.
When administered topically, for example, via inhalation, etc., the aforementioned additives as used herein include any of pharmaceutical ingredients known in the art, such as solution adjuvants, stabilizers, buffers, suspending agents, emulsifying agents, and preservatives. Embodiments of inhalants include aerosols. Aerosol-producing techniques are any of types including a spraying type wherein active drug ingredients are packed together with propellants such as fluorocarbon alternatives into a sealed container and sprayed, and a nebulizer or atomizer type using a pressured gas, such as carbon dioxide and nitrogen, filled in a container different from that for active drug ingredients.
For said aerosols, representatives of pharmaceutical ingredients such as propellants, solution adjuvants, stabilizers, buffers, suspending agents, emulsifying agents, and preservatives, include chlorine-free fluorinated hydrocarbons [e.g., 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), etc.], alcohol, propylene glycol, polyethylene glycol, Polysorbate 80, glycerin, egg yolk lecithin, soybean lecithin, xcex1-tocopherol, ascorbic acid, benzalkonium chloride, chlorobutanol, etc. Besides, when the aerosols are prepared in the form of nebulizers or atomizers as aforementioned, the pharmaceutical ingredients as used may include water for injection, purified water, etc. Further, the inhalants may also be prepared in the form of not only sprays wherein any of the above-defined propellants is used, nebulizers or atomizers, but also powders. Such powder inhalants can be in any of forms similar to available powder inhalants in the art (e.g., INTAL (registered trademark) capsule and metered-dose inhaler: SPINHALER (registered trademark); for administration of sodium chromoglicate).
In addition to the aforementioned inhalants, the compounds of the present invention may be administered topically in the form of ointments, transdermic patches, solutions for external use, eyedrops, nose drops or suppositories. Such topical pharmaceutical preparations may suitably contain pharmaceutical ingredients as disclosed in the aforementioned xe2x80x9cIyakuhin Tenkabutsu Handbook (Handbook of PHARMACEUTICAL EXCIPIENTS)xe2x80x9d, xe2x80x9cIyakuhin Tenkabutsu Jiten (Pharmaceutical Excipient Dictionary)xe2x80x9d, etc.
Desired oral drugs, injections or drugs for topical applications (including inhalants) comprising the compound of the present invention in admixture with the aforementioned ingredient can be prepared according to manufacturing methods known per se, for example, those described in The 13th Pharmacopoeia of Japan (JPXIII) or appropriately modified ones.
The pharmaceutical compositions (drugs) of the present invention are administered to mammals, particularly including human. The doses of these compounds or salts thereof are usually about 0.1 to 1,000 mg (per day), preferably about 0.1 to 500 mg (per day) for oral administration; usually about 0.01 to 200 mg (per day), preferably about 0.05 to 100 mg (per day) for injection; and usually about 0.01 to 200 mg (per day), preferably about 0.05 to 100 mg (per day) for topical applications. specific administration routes and dose levels (including the optimal dose) for any particular patient will be employed depending upon a variety of factors including the patient""s conditions (general health, the severity of the particular disease or symptom undergoing therapy, the presence or absence of complications thereof, etc.), the age, sex, body weight, and the like.